Loss of Placental P-Glycoprotein May Be a Common Pathophysiologic Pathway for First Trimester Spontaneous Miscarriages.

INTRODUCTION: P-glycoprotein the highly conserved mammalian adenosine triphosphate-binding cassette transmembrane multidrug protein transporter is involved in peri-implantation events and fetal placental development. Greater expression in early versus late pregnancy and localization in both syncytio- and cytotrophoblast indicate that P-glycoprotein transports substances across the uterine epithelium during early pregnancy and protects the conceptus from toxic substances during implantation and early embryogenesis. We hypothesized that P-glycoprotein is involved in the physiologic maintenance of early pregnancy and that P-glycoprotein dysregulation may be involved in early pregnancy pathologies. METHODS: First trimester dilation and curettage specimens were selected retrospectively from the archives of the Department of Pathology from spontaneous miscarriages (n = 36) and elective termination of pregnancy (n = 20). Two P-glycoprotein specific monoclonal antibodies JSB1and C219 were used on formalin-fixed, paraffin-embedded 5µ tissue sections. The location, intensity, and percentage of P-glycoprotein chorionic villous immunostaining were semiquantitated. RESULTS: Spontaneous miscarriages demonstrated absence or significant reduction in P-glycoprotein compared to elective terminations; 75% (27/36) showed total absence of P-glycoprotein, 19% (7/36) showed only rare villi with discontinuous immunostaining, and 6% (2/36) showed weak immunostaining. In contrast, 90% of elective terminations (18/20) showed positive immunostaining for P-glycoprotein and only 10% (2/20) showed loss of P-glycoprotein expression (P < .0001). DISCUSSION: We report a dramatic loss/decrease of P-glycoprotein in first trimester spontaneous miscarriages. This finding in conjunction with the known high expression of P-glycoprotein in normal first trimester placental tissues suggests an important role of P-glycoprotein in the maintenance of early pregnancy.

Loss of PTEN and Increased pAKT Expression Distinguishes Aggressive Low-grade Neuroendocrine Tumors.

A major problem in neuroendocrine pathology is the identification and separation of aggressive low-grade neuroendocrine tumors (LGNETs) from those with a benign or more indolent behavior. Presently there are no known morphologic or molecular parameters which can predict how localized LGNETs will behave. The phosphatase and tensin homolog (PTEN) gene negatively regulates the PI3K-AKT-mTOR pathway and inhibits neoplastic cell survival and proliferation and has recently been identified as a neuroendocrine tumor differentiation marker. We hypothesized loss of PTEN may also identify LGNETs that demonstrate aggressive behavior. We studied PTEN and pAKT expression in 18 LGNETs using specific monoclonal antibodies. Follow up was obtained for a minimum of five years on all patients. 8/18 cases had strong PTEN expression and showed no evidence of disease on >5 years follow-up. 10 cases demonstrated loss of PTEN expression; 9/10 had positive pAKT expression, and 7/9 had recurrence and/or metastases. Lung and appendiceal LGNETs uniformly had high PTEN expression and a markedly better prognosis than their gastroenteropancreatic (GEP) counterparts. Loss of PTEN correlated significantly with the positive expression of pAKT (P=0.0027) and aggressive behavior of LGNETs (p=0.0002). Loss of PTEN and increased pAKT correlated with the metastatic potential of LGNETs (p=0.0011 and 0.0248 respectively). Loss of PTEN and increased pAKT expression distinguishes aggressive LGNETs from those with more indolent behavior.

Cytological diagnosis of adult T-cell leukemia/lymphoma in sputum.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive T-cell leukemia/lymphoma that has been linked to infection by the human T-cell lymphotropic virus type 1 (HTLV-1). ATLL can involve multiple organs including the respiratory airway. A 53-year-old Trinidadian woman presented with productive cough and progressive shortness of breath. Her past medical history included duodenal strongyloidosis, skin rash, and hypercalcemia. Radiological studies showed increased interstitial markings. Sputum cytology showed atypical pleomorphic, small-to-medium-sized, lobated lymphocytes with irregular and hyperchromatic nuclei resembling "flower cells" which were CD3±/CD20- by immunocytochemistry. A lung biopsy showed interstitial, peribronchiolar, and subpleural infiltration by a CD3±/CD25± atypical lymphocytic infiltrate. Together with peripheral blood findings and positive HTLV-1 serology, the diagnosis of ATLL was made. We suggest that sputum evaluation in patients with ATLL risk factors can be diagnostic.

Postirradiation Leiomyosarcoma of Rectum Presenting as a Polyp: Case Report and Review of the Literature.

Radiation-induced leiomyosarcomas of the gastrointestinal tract are rare. Very few cases have been documented to date. The histological similarity to gastrointestinal stromal tumor has raised doubts if many of the cases originally reported to be leiomyosarcoma before the widespread use of CD117 were indeed gastrointestinal stromal tumors. We present a case of post-irradiation leiomyosarcoma presenting as a rectal polyp and review the literature.

Isolated fibromuscular dysplasia of the coronary ostium: a rare cause of sudden death. Case report and review of the literature.

We present a unique case of sudden death in a 21-year-old man with history of cocaine use and a solitary fibromuscular dysplastic lesion completely occluding the left coronary artery ostium. We document intimal proliferation of myofibroblasts at the opening of the left coronary ostium without other concomitant lesions. This report discusses the gross and histologic features of the lesion, explores in careful detail the possible etiologies, and gives a comprehensive literature review of isolated coronary ostial fibromuscular dysplasia presenting with sudden death.

A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: a potential therapeutic effect of HAART in multiple myeloma.

The impact of highly active anti-retroviral therapy (HAART) in multiple myeloma (MM) is unknown. Ten HIV+ and 28 HIV-negative patients were retrospectively identified out of 262 cases of MM diagnosed at Kings County Hospital Center since the introduction of HAART in 1996. The HIV+ MM patients on HAART had superior overall survival (OS) (Fisher exact, p=0.008; log-rank, p=0.012) and progression free survival (PFS) (Fisher exact, p=0.007; log-rank, p=0.009) than the HIV-negative MM patients. HAART alone blocked the production of serum M-protein. We propose that HARRT should be explored for the treatment of both HIV+ and HIV-negative MM patients.

Loss of Foxp3 is associated with CD30 expression in the anaplastic large cell subtype of adult T-cell leukemia/lymphoma (ATLL) in US/Caribbean patients: potential therapeutic implications for CD30 antibody-mediated therapy.

Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor α (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T-cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients' clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient's second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies.

Attributes of brain metastases from breast and lung cancer.

BACKGROUND: Most brain metastases arise from breast and lung cancers. Few studies compare the brain regions they involve, their numbers and intrinsic attributes. METHODS: Records of all patients referred to Radiation Oncology for treatment of symptomatic brain metastases were obtained. Computed tomography (n = 56) or magnetic resonance imaging (n = 72) brain scans were reviewed. RESULTS: Data from 68 breast and 62 lung cancer patients were compared. Brain metastases presented earlier in the course of the lung than of the breast cancer patients (p = 0.001). There were more metastases in the cerebral hemispheres of the breast than of the lung cancer patients (p = 0.014). More breast than lung cancer patients had cerebellar metastases (p = 0.001). The number of cerebral hemisphere metastases and presence of cerebellar metastases were positively correlated (p = 0.001). The prevalence of at least one metastasis surrounded with >2 cm of edema was greater for the lung than for the breast patients (p = 0.019). The primary tumor type, rather than the scanning method, correlated with differences between these variables. CONCLUSIONS: Brain metastases from lung occur earlier, are more edematous, but fewer in number than those from breast cancers. Cerebellar brain metastases are more frequent in breast cancer.

Correlation between the proportion of breast volume involved by locally advanced tumors and invasion of the skin and posterior structures.

AIM: To evaluate any differences between the percentages of involved breast volume, pathologic attributes, and tumor marker expression of T3 and T4a-c tumors in locally advanced breast cancers (BC). METHODS: All patients with T3N > 0 and T4a-c BC without evidence of distant metastasis (M0), presenting to the Breast Clinic from 1980 to 2010, were examined to determine whether their BC's involved ≥ 50% of their breast volumes, defined by gross replacement of at least one hemisphere. Core needle biopsy or post-mastectomy specimens from tumors involving a known percent of breast volume were evaluated for: (1) pathological grades and lympho-vascular invasion (LVI); (2) hormone receptor (ER/PR) expression > 0; and (3) epidermoid growth factor 2 (her2) over-expression (3+) by immune-histochemical staining or fluorescent in situ hybridization. RESULTS: The data base included 98 patients with T3N> 0 M0 and 120 with T4a-c, any N disease, M0 disease. T3 tumor masses involved 50% or more of the breast in 23/98 (24%), and T4a-c tumors 65/120 (54%) (P < 0.001). Only 1% of T3 tumors and 23% of T4a-c tumors presented with total breast replacement. There were no significant differences between the pathological attributes and marker expression of the T3 and T4a-c tumors. CONCLUSION: These data suggest that erosion of the overlying skin or underlying chest wall by some BC may be due to neglect and delay, rather than inherent biological aggressiveness.

Sebaceous carcinoma of the oral cavity: a case report and review of the literature.

We report the clinical and pathologic features of an intraoral sebaceous carcinoma and review the literature. The intraoral buccal mucosal tumor from a 50-year-old man was a poorly differentiated carcinoma with sebaceous differentiation and expression of androgen receptor. Fordyce granules and a minor salivary gland with a duct were identified in vicinity to the tumor. We discuss the differential diagnosis and histogenesis. The patient underwent surgery and adjuvant radiation therapy.

Localized nasal cavity, sinus, and massive bilateral orbital involvement by human T cell leukemia virus 1 adult T cell lymphoma, with epidermal hypertrophy due to mite infestation.

HTLV1 adult T cell lymphoma occurs tends to be widely disseminated and aggressive, with only brief responses to chemotherapy. Aside from cervical adenopathy, involvement of head and neck structures is uncommon and orbital involvement rare.We report a case of nasal cavity HTLV lymphoma with massive bilateral orbital involvement and proptosis, resulting in complete left and partial right eye amaurosis. No other sites of disease were found. Response to chemotherapy was rapid and complete, with almost complete restoration of vision and oculo-motor function; the patient has remained in remission for one year. An associated problem was striking bilateral hypertrophic, hyperkeratotic eyelid and breast lesions due to mite infestation.

An in-depth look at Leydig cell tumor of the testis.

Leydig cell tumor (LCT) is a rare tumor of the male testicular interstitium. This article provides an overview of the major pathologic manifestations of LCT of the testis; patient characteristics; clinical, radiologic, and laboratory features; prognosis; and management. LCTs of the testis are frequently hormonally active, leading to either feminizing or virilizing syndromes. The tumor is usually benign, but malignant variants can occur. The pathologic diagnosis of LCT is usually made based on morphologic characteristics of the tumor cells. The significance of Reinke crystals in the diagnosis of LCT both cytologically and histologically is underscored. Pathologists have to be familiar with the diagnostic histopathologic features, immunohistochemical panel of this tumor, and its principal differential diagnoses to prevent tumor misdiagnosis.

Haymaker gene expression in malignant and normal gynecologic tissues.

We previously reported that cell lines established from human carcinomas and leukemias/lymphomas expressed high levels of an intracellular membrane-bound protein, Haymaker, whereas cell lines derived from non-malignant connective tissue cells and lymphoid cells expressed low levels of this gene product. To determine whether these findings reflect neoplastic transformation or, alternatively, tissue specificity, we examined by immunohistochemical and molecular methods the expression of Haymaker in gynecologic organs with and without tumor. A highly specific, affinity-purified rabbit polyclonal antibody against a 25-mer Haymaker peptide was used for immunohistochemical staining and morphometric analysis of 85 tissue specimens. Immunohistochemical studies demonstrate, for the first time, that Haymaker protein is highly expressed in epithelial cells of the endometrium of the normal uterus and to a somewhat lesser extent in the mucosa of the normal vagina and cervix, but is poorly expressed or absent in cells of the connective tissue and smooth muscle strata of these organs (p < 0.005). Significant differences in Haymaker expression, as assessed by immunohistochemistry, between malignant and normal gynecologic tissues were not observed (p = 0.27). The expression of Haymaker protein does not appear, therefore, to be a marker of malignant transformation of the epithelium of gynecologic organs but rather distinguishes both normal and malignant epithelial cells from normal connective tissue and smooth muscle cells.

Plasma cell tumors in HIV-positive patients: report of a case and review of the literature.

Plasma cell tumors show an increased incidence in HIV-positive patients. The cases reported in the literature suggest that plasma cell tumors occur in a younger age group than that encountered in the general population. Pathologically, many of these tumors show a plasmablastic morphology. Plasma cell tumors in HIV-positive patients may present at unusual sites and progress rapidly to involve multiple sites, including the soft tissues and viscera. The prognosis is generally poor. These features may be related to a combination of factors, including immunodeficiency, oncogenic viruses, and altered cytokine milieu in these patients. A case of plasma cell tumor in an HIV-positive patient is presented.

Overexpression of neural cell adhesion molecule in regenerative muscle fibers in 3-hydroxy-3-methylglutaryl coenzyme: A reductase inhibitor-induced rhabdomyolysis.

Skeletal muscle degeneration is a side effect of cholesterol-lowering hydroxymethylglutaryl coenzyme A reductase inhibitors. The expression of the cell-cell adhesion proteins, neural cell adhesion molecule and neural-cadherin was studied in a case of rhabdomyolysis induced by the hydroxymethylglutaryl coenzyme A reductase inhibitor cerivastatin. Neural cell adhesion molecule and N-cadherin participate in the interactions of muscle cells during skeletal myogenesis. In the adult muscle, neural cell adhesion molecule is restricted to neuromuscular sites but is re-expressed in denervated muscle and in rhabdomyolysis. Our results show expression of neural cell adhesion molecule in regenerative skeletal muscle fibers but not in degenerated or unaffected fibers in cerivastatin-induced rhabdomyolysis. In contrast, N-cadherin was not expressed. The presence of apoptotic cells was studied by a fluorescence-based Tdt-mediated dUTP nick-end labeling in the same sections. Apoptosis was detected in degenerative fibers and inflammatory cells but not in regenerative fibers. We hypothesize that the expression of neural cell adhesion molecule in regenerative fibers may have a protective role against apoptosis during rhabdomyolysis. Cerivastatin-induced rhabdomyolysis appears to have common features with rhabdomyolysis of other causes. The immunohistochemical study of neural cell adhesion molecule can serve as an additional tool in the evaluation of muscle regeneration in rhabdomyolysis.

Phase II study of interferon gamma in malignant carcinoid tumors (E9292): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the safety and efficacy of treatment with gamma interferon (IFNgamma) in patients with metastatic carcinoid tumor. PATIENTS AND METHODS: 51 patients were enrolled on this Phase II Eastern Cooperative Oncology Group (ECOG) study. Seventy five percent of them had hormonally active tumors. Treatment consisted of IFNgamma subcutaneously at a daily dose of 0.1 mg/m(2). Patents were evaluated for toxicity weekly for the first month and monthly thereafter; response was determined radiologically every 8 weeks. RESULTS: Patients received treatment with IFNgamma for a median of 17.9 weeks (range 2-175). Toxicity was generally mild and expected: 61% experienced noninfected fever and 21% developed granulocytopenia. Three patients (6%) had a partial response; there were no complete responses. Median time to progression was 5.5 months (95% confidence interval 3.9-11.1). The 1-year progression free rate was 28% (13.4-43.4%). Median survival was 42 months, with a 1-year survival rate of 67% (53.3-80%). DISCUSSION: This Phase II study demonstrated that therapy with IFNgamma in patients with metastatic carcinoid tumor was well-tolerated, but did not produce significant antitumor effects. The overall results were somewhat comparable to those previously seen with alpha interferons as well as cytotoxic drugs.

Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms.

Genetic alteration and loss of expression of tumor suppressor gene PTEN has been found in carcinomas of the breast, prostate, and endometrium, as well as in gliomas. PTEN expression in neural crest/neuroendocrine (NC/NE) tissues and in neoplasms has not been reported. This study examines PTEN expression in embryonal, fetal, and adult tissues by immunohistochemistry. The authors found high PTEN expression in embryonal, fetal, and adult NC/NE tissues. The authors also study the PTEN expression in NC/NE neoplasms (N = 37), including 5 melanocytic nevi, 2 melanomas, 9 carcinoids, 2 moderately differentiated neuroendocrine carcinomas, 13 poorly differentiated neuroendocrine carcinomas, 2 paragangliomas, 2 pheochromocytomas, 2 medullary thyroid carcinomas, and 1 neuroblastoma. All carcinoid tumors and melanocytic nevi showed moderate or strong immunostaining for PTEN. In contrast, the majority of poorly differentiated neuroendocrine carcinomas (7 of 13) were negative for PTEN (54%); the remainder showed diminished reactivity. The two melanomas studied were also negative for PTEN immunostaining. The paragangliomas, pheochromocytomas, medullary thyroid carcinomas, and neuroblastoma all showed a strong PTEN stain. The authors postulate that PTEN is a differentiation marker for NC/NE tissue and tumors and that loss of PTEN expression may represent an important step in the progression of NE tumors.